Cyclosporine and FK506 differentially regulate the sarcolemmal Na(+)-K(+) pump.

ABSTRACT

Cyclosporine A (CsA) and FK506, important immunosuppressants, have been shown to inhibit the enzymatic equivalent of the Na(+)-K(+) pump (Na(+), K(+)-ATPase) in renal tissue. A similar effect in the heart may contribute to the adverse effects of these agents that include calcification, contractile dysfunction, and altered calcium handling. However, inhibition of the pump has not been demonstrated in cardiac myocytes. We isolated single ventricular myocytes from control rabbits and from rabbits administered CsA or FK506 for 1 week. Na(+)-K(+) pump current (I(p)) was measured using the whole-cell patch-clamp technique. When patch pipettes contained Na(+) in a concentration ([Na](pip)) near physiological intracellular levels mean I(p) of cardiac myocytes from rabbits with serum CsA levels within the therapeutic range was significantly lower than mean I(p) of cardiac myocytes from controls. Treatment had no effect on I(p) measured using a [Na](pip) expected to nearly saturate intracellular binding sites. The CsA-induced inhibition of I(p) was dependent on the K(+) concentration in pipette solutions. Mean I(p) in myocytes from rabbits with serum levels of FK506 within the therapeutic range was similar to mean I(p) in myocytes from controls, whereas FK506 in a dose inducing serum levels severalfold above the therapeutic range caused significant pump inhibition. Using ion-sensitive microelectrodes we showed the intracellular Na(+) activity in papillary muscles isolated from rabbits treated with CsA was significantly higher than in papillary muscles from control rabbits, indicating that CsA causes pump inhibition in intact myocytes with a physiological intracellular milieu.